Fangxu Tang

High Dose Zinc Supplementation Induces Hippocampal Zinc Deficiency and Memory Impairment with Inhibition of BDNF Signaling

Zinc ions highly concentrate in hippocampus and play a key role in modulating spatial learning and memory. At a time when dietary fortification and supplementation of zinc have increased the zinc consuming level especially in the youth, the toxicity of zinc overdose on brain function was underestimated. In the present study, weaning ICR mice were given water supplemented with 15 ppm Zn (low dose), 60 ppm Zn (high dose) or normal lab water for 3 months, the behavior and brain zinc homeostasis were tested. Mice fed high dose of zinc showed hippocampus-dependent memory impairment. Unexpectedly, zinc deficiency, but not zinc overload was observed in hippocampus, especially in the mossy fiber-CA3 pyramid synapse. The expression levels of learning and memory related receptors and synaptic proteins such as NMDA-NR2A, NR2B, AMPA-GluR1, PSD-93 and PSD-95 were significantly decreased in hippocampus, with significant loss of dendritic spines. In keeping with these findings, high dose intake of zinc resulted in decreased hippocampal BDNF level and TrkB neurotrophic signaling. At last, increasing the brain zinc level directly by brain zinc injection induced BDNF expression, which was reversed by zinc chelating in vivo. These results indicate that zinc plays an important role in hippocampus-dependent learning and memory and BDNF expression, high dose supplementation of zinc induces specific zinc deficiency in hippocampus, which further impair learning and memory due to decreased availability of synaptic zinc and BDNF deficit.

The predictive value of serum squamous cell carcinoma antigen in patients with cervical cancer who receive neoadjuvant chemotherapy followed by radical surgery: a single-institute study.

Objective Neoadjuvant chemotherapy (NACT) could affect the levels of squamous cell carcinoma antigen (SCC-Ag). This study evaluates the predictive value of pre- and posttreatment SCC-Ag levels in patients with cervical cancer who were treated with NACT followed by radical surgery. Methods A total of 286 patients with Stage IB1-IIIB squamous cell carcinoma of the uterine cervix who were treated with NACT followed by radical hysterectomy were analyzed retrospectively. The relationship between SCC-Ag levels, the clinicopathologic parameters, the response to NACT and the three-year survival rate was investigated. Results The levels of SCC-Ag were elevated (>3.5 ng/mL) in 43.8% of patients before NACT, and 13.0% of patients after NACT. Pre- and posttreatment levels of SCC-Ag correlated with the response to NACT (P = 0.010, and P<0.001), deep stromal infiltration (P = 0.041, and P = 0.006), and lymph node status (P<0.001, and P<0.001). In the multivariate analysis, the elevated pretreatment level of SCC-Ag was demonstrated to be an independent risk factor for Lymph node metastases (P<0.001). Patients with both pre- and posttreatment SCC-Ag levels ≤3.5 ng/mL showed the best 3-year disease-free survival (DFS) and 3-year overall survival (OS) compared with patients with either pre- or posttreatment levels >3.5 ng/mL (P<0.001, and P<0.001, respectively). A multivariate analysis showed that posttreatment SCC-Ag levels were a strong independent predictor of OS (P = 0.001) and DFS (P = 0.012). Conclusion Elevated pretreatment levels of SCC-Ag (>3.5 ng/mL) indicated a poor response to NACT and a higher risk of lymph node metastases. Elevated posttreatment levels of SCC-Ag were correlated with poor DFS and OS.

Association of 42 SNPs with genetic risk for cervical cancer: an extensive meta-analysis

BackgroundA large number of single nucleotide polymorphisms (SNPs) associated with cervical cancer have been identified through candidate gene association studies and genome-wide association studies (GWAs). However, some studies have yielded different results for the same SNP. To obtain a more comprehensive understanding, we performed a meta-analysis on previously published case–control studies involving the SNPs associated with cervical cancer.MethodsElectronic searches of PubMed and Embase were conducted for all publications about the association between gene polymorphisms and cervical cancer. One-hundred and sixty-seven association studies were included in our research. For each SNP, three models (the allele, dominant and recessive effect models) were adopted in the meta-analysis. For each model, the effect summary odds ratio (OR) and 95% CI were calculated. Heterogeneity between studies was evaluated by Cochran’s Q test. If the p value of Q test was less than 0.01, a random effect model was used; otherwise, a fixed effect model was used.ResultsThe results of our meta-analysis showed that: (1) There were 8, 2 and 8 SNPs that were significantly associated with cervical cancer (P < 0.01) in the allele, dominant and recessive effect models, respectively. (2) rs1048943 (CYP1A1 A4889G) showed the strongest association with cervical cancer in the allele effect model (1.83[1.57, 2.13]); in addition, rs1048943 (CYP1A1 A4889G) had a very strong association in the dominant and recessive effect model. (3) 15, 11 and 10 SNPs had high heterogeneity (P < 0.01) in the three models, respectively. (4) There was no published bias for most of the SNPs according to Egger’s test (P < 0.01) and Funnel plot analysis. For some SNPs, their association with cervical cancer was only tested in a few studies and, therefore, might have been subjected to published bias. More studies on these loci are required.ConclusionOur meta-analysis provides a comprehensive evaluation of cervical cancer association studies.

Case-Control Study of Diet in Patients with Cervical Cancer or Precancerosis in Wufeng, a High Incidence Region in China

PURPOSE To investigate the diet of patients with cervical cancer and precancerosis in the Wufeng area, a high- incidence region in China. METHODS In the case group, 104 patients diagnosed with cervical cancer or cervical intraepithelial neoplasias (CINII/III) were recruited from the Wufeng area. Nine hundred thirty-six healthy women were selected from the same area as the matched controls. A questionnaire, which included questions about general lifestyle conditions, smoking and alcohol status, source of drinking water, green tea intake, and diet in the past year, was presented to all participants. RESULTS Green tea intake (P=0.022, OR=0.551, 95% CI=0.330-0.919) and vegetable intake (P=0.035, OR=0.896, 95% CI=0.809-0.993) were identified as protective factors against cervical cancer or CINII/III. There was no indication of any associations of other lifestyle factors (smoking status, alcohol status, source of drinking water) or diet (intake of fruit, meat/egg/milk, soybean food, onion/garlic, staple food and pickled food) with cervical cancer. CONCLUSIONS The results suggest that eating more fresh vegetables and drinking more green tea may help to reduce the risk of cervical cancer or CINII/III in people of the Wufeng area.

Outcome of international Federation of gynecology and obstetrics stage IIb cervical cancer from 2003 to 2012: an evaluation of treatments and prognosis: a retrospective study.

Objective To compare the clinical outcomes of patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIB cervical carcinoma receiving neoadjuvant chemotherapy followed by radical hysterectomy (RH) with those of patients receiving chemoradiation therapy (CRT) alone. Methods We retrospectively reviewed the medical records of patients with FIGO stage IIB cervical carcinoma. A total of 621 patients were eligible for the study according to the surgery-based or radiotherapy-based treatment; 285 patients received cisplatin-based neoadjuvant chemotherapy (NACT) followed by RH, and 336 patients underwent sequential or concurrent chemoradiation. The disease-free survival, overall survival, recurrence rates, and late complications were compared. Cox regression analysis was used to identify potential prognostic factors. Results Complete or partial response was seen in 77.6% (221/285) of the NACT-treated patients. Disease-free survival and overall survival rates of the patients who had NACT-sensitive responses were significantly higher than those who did not response (P = 0.021 and P = 0.008). Overall survival rates in the NACT + RH group were comparable with the concurrent chemoradiotherapy or chemoradiation groups (P > 0.05). Neoadjuvant chemotherapy followed by RH significantly decreased the recurrence rate (22.6% vs 35.5%), resulted in fewer treatment-related complications, and ultimately improved survival when compared with concurrent CRT. A survival benefit was observed for 63.9% of the patients in the NACT + RH group without adjuvant radiotherapy or CRT. Conclusions Compared with concurrent chemoradiotherapy, NACT followed by RH achieved comparable survival outcomes for patients with FIGO stage IIB cervical cancer. This treatment method was significantly effective at reducing radiotherapy rates and complications, and it is worthy of recommending for younger patients.

Genome-wide association study identifies four SNPs associated with response to platinum-based neoadjuvant chemotherapy for cervical cancer.

To identify genomic markers associated with the response to neoadjuvant chemotherapy (NACT) in patients with cervical cancer, we performed a three-stage genome-wide association study (GWAS) in the Han Chinese population. A total of 596 patients with stage IA2-IIIB cervical cancer were enrolled in this study. One single nucleotide polymorphism (SNP) (rs6812281, per allele OR = 2.37, P = 9.0 × 10−9) located at 4q34.3 reached GWAS significance (P < 5.0 × 10−8). Another three SNPs, rs4590782 (10q26.2, P = 1.59 × 10−5, per allele OR = 0.48), rs1742101 (14q32.11, P = 7.11 × 10−6, per allele OR = 0.52), and rs1364121 (16q23.3, P = 3.15 × 10−6, per allele OR = 1.98), exhibited strong evidence of associations with response to neoadjuvant chemotherapy. Patients with a C allele (CT + CC) of rs4590782 had better 5-year overall survival rates (82.9% vs. 75.8%, P = 0.083) and 5-year disease-free survival rate (80.8% vs. 72.7%, P = 0.021) than those without a C allele. Our findings help to characterize the genetic etiology of the response to neoadjuvant chemotherapy in patients with cervical cancer.

Establishing a Nomogram for Stage IA-IIB Cervical Cancer Patients after Complete Resection.

BACKGROUND This study aimed to establish a nomogram by combining clinicopathologic factors with overall survival of stage IA-IIB cervical cancer patients after complete resection with pelvic lymphadenectomy. MATERIALS AND METHODS This nomogram was based on a retrospective study on 1,563 stage IA-IIB cervical cancer patients who underwent complete resection and lymphadenectomy from 2002 to 2008. The nomogram was constructed based on multivariate analysis using Cox proportional hazard regression. The accuracy and discriminative ability of the nomogram were measured by concordance index (C-index) and calibration curve. RESULTS Multivariate analysis identified lymph node metastasis (LNM), lymph-vascular space invasion (LVSI), stromal invasion, parametrial invasion, tumor diameter and histology as independent prognostic factors associated with cervical cancer survival. These factors were selected for construction of the nomogram. The C-index of the nomogram was 0.71 (95% CI, 0.65 to 0.77), and calibration of the nomogram showed good agreement between the 5-year predicted survival and the actual observation. CONCLUSIONS We developed a nomogram predicting 5-year overall survival of surgically treated stage IA-IIB cervical cancer patients. More comprehensive information that is provided by this nomogram could provide further insight into personalized therapy selection.

Optimal pathological response indicated better long-term outcome among patients with stage IB2 to IIB cervical cancer submitted to neoadjuvant chemotherapy

The role of pathological response in long-term outcome is still unclear in cervical cancer patients treated with neoadjuvant chemotherapy (NACT) in China. This study aimed to investigate the effect of optimal pathologic response (OPR) on survival in the patients treated with NACT and radical hysterectomy. First, 853 patients with stage IB2-IIB cervical cancer were included in a retrospective analysis; a Cox proportional hazards model was used to investigate the relationship between pathological response and disease-free survival (DFS). In the retrospective database, 64 (7.5%) patients were found to have achieved an OPR (residual disease <3 mm stromal invasion); in the multivariate Cox model, the risk of death was much greater in the non-OPR group than in the OPR group (HR, 2.61; 95%CI, 1.06 to 6.45; P = 0.037). Next, the role of OPR was also evaluated in a prospective cohort of 603 patients with cervical cancer. In the prospective cohort, 56 (9.3%) patients were found to have achieved an OPR; the log-rank tests showed that the risk of recurrence was higher in the non-OPR patients than in the OPR group (P = 0.05). After combined analysis, OPR in cervical cancer was found to be an independent prognostic factor for DFS.

Young Cervical Cancer Patients May Be More Responsive than Older Patients to Neoadjuvant Chemotherapy Followed by Radical Surgery

Objective To evaluate the effects of age and the clinical response to neoadjuvant chemotherapy (NACT) in patients with cervical cancer who received neoadjuvant chemotherapy followed by radical surgery. Methods A total of 1,014 patients with advanced cervical cancer who received NACT followed by radical surgery were retrospectively selected. Patients were divided into young (aged ≤35 years, n = 177) and older (aged >35 years, n = 837) groups. We compared the short-term responses and survival rates between the groups. The five-year disease-free survival (DFS) and overall survival (OS) rates were stratified by age, NACT response, and FIGO stage. Results The overall response rate was 86.8% in the young group and 80.9% in the older group. The young patients had an earlier FIGO stage (P<0.001), a higher rate of adenocarcinoma (P = 0.022), and more lymph node metastasis (P = 0.033) than the older patients. The presence of adenocarcinoma as the histological type (P = 0.024) and positive lymph node metastasis (P<0.001) were identified as independent risk factors for survival. When stratified by age and clinical response, young patients with no response to NACT had a worse clinicopathological condition compared with the other subgroups. Compared with non-responders, responders to NACT had a higher five-year DFS rate (80.1% versus 71.8%; P = 0.019) and OS rate (82.6% versus 71.8%; P = 0.003) among the young patients but not among the older patients. Conclusions Responders to NACT aged 35 years or younger benefitted the most from NACT, while the young non-responders benefitted the least. Age might represent an important factor to consider when performing NACT in patients with cervical cancer.

Adjuvant chemotherapy after surgery can improve clinical outcomes for patients with IB2-IIB cervical cancer with neoadjuvant chemotherapy followed by radical surgery

The aim of the study is to evaluate the efficacy of postoperative treatments based on pathological response for cervical cancer patients who received neoadjuvant chemotherapy (NACT) followed by radical surgery. Firstly, a total of 756 cervical squamous cell cancer (SCC) patients with FIGO IB2-IIB were included in this retrospective study. Then data from a prospective cohort of 393 patients was employed for further validation. Overall survival (OS) and disease-free survival (DFS) were assessed. In the retrospective study, SCC patients who accepted adjuvant chemotherapy after radical surgery had a relatively better OS than those who received no therapy (P = 0.08, HR = 0.57). The result was more noticeable in the prospective cohort study (P = 0.006, HR = 0.28). In the combined analysis, adjuvant chemotherapy improved clinical outcomes compared with no therapy (P = 0.002 and 0.04 for OS and DFS). Particularly for patients with extra-cervical residual disease, adjuvant chemotherapy improved OS (log-rank P = 0.008, 0.004 and 0.001 in the retrospective, prospective and combined studies). Optimal response patients had good outcomes even without therapy. Our study indicates that adjuvant chemotherapy can benefit clinical outcomes for SCC patients with NACT followed by radical surgery, especially those with extra-cervical residual disease. For optimal response patients, there may be no need for further treatment. This finding needs to be validated in more future studies.